It is widely recognized that the endothelium is affected by the metabolic state of the organism, and endothelial function can also influence systemic metabolism. This program project renewal application brings together five productive project leaders who have a long history of collaboration to investigate mechanisms that underlie how the endothelium is both affected by and contributes to metabolic homeostasis. Project 1 will examine the mechanism by which endothelial cells switch from aerobic respiration to anaerobic glycolysis under conditions that stimulate vascular growth (i.e. hypoxia and pseudo-hypoxia) by focusing on a HIF1a-regulated microRNA that regulates the expression of mitochondrial respiratory complex proteins. Project 2 will examine mechanisms of redox regulation of cell signaling in vascular function and how these processes are perturbed by endothelial cell exposure to oxidants and reactive lipids that are associated with inflammation and metabolic disease. Project 3 will examine the functional interplay between endothelial function and inflammation in adipose tissue and assess how these processes influence systemic metabolism by focusing on mouse models that over- and under-express the adipocyte-derived cytokine adiponectin. Project 4 will also examine the interrelationship between the endothelium and inflammation in fat by measuring microvascular function and inflammatory markers in the fat of obese individuals before and after extensive weight loss resulting from bariatric surgery. Project 5 will examine the role of mitochondrial homeostasis in endothelial and inflammatory cells isolated from patients with Type 2 diabetes mellitus. This conceptually cohesive program focuses on an under-explored, yet clinically important, area of endothelial cell biology. With these proposed studies, we hope develop a better understanding of how endothelium functions at the interface of cardiovascular disease and metabolic dysfunction.